The overall goal of this proposal is to further our understanding of how photosensitizer structure affects the biological response to photodynamic therapy (PDT) and to use this information to develop an approach for rational design of photosensitizers for PDT. This will be done by utilizing extensive information already developed in our laboratory and others and applying similar and expanded in vivo and in vitro studies to selected photosensitizer series. The specific aims are: (1) To expand an existing in vivo quantitative structure activity (QSAR) study of a congeneric series of pyropheophorbide ether photosensitizers for photodynamic therapy to address issues for both efficacy and selectivity. (2) To prepare additional congeneric series of compounds which differ in critical ways from the pyropheophorbide ethers, and to determine whether similar QSAPs exist. (3) To explore in vivo the possible importance of specific, optimal intracellular binding sites in both the pyropheophorbide ether series and the new series emerging from Aim 2. (4) To use the existing and new data as they are developed in Aims 1, 2, 3 and Project III to carry out molecular modeling using 3D QSAR as well as modeling specific binding to site II of albumin (benzodiazepine site), the peripheral benzodiazepine receptor and other important binding sites identified in Project III. (5) To introduce into clinical trials the optimal pyropheophorbide ether (hexyl) identified in the QSAR study of a congeneric series of pyropheophorbide ether.